Arylethylamine compounds

ABSTRACT

The invention relates to a compound selected from those of formula (I): ##STR1## in which Ar&#39;, R 1  and R 2  are as defined in the specification, an optical isomer, 
     and an addition salt thereof with a pharmaceutically-acceptable acid or base. 
     Medicinal product which is useful in treating or in preventing a disorder of the melatoninergic system.

The present invention relates to new arylethylamine compounds, toprocesses for the preparation thereof, and to pharmaceuticalcompositions containing them.

A certain number of arylethylamine compounds having an indole nucleusare described as being agonists or antagonists of melatonin, both inpatents GB 219 2001 and WO 89/01472, and in the publications J. Med.Chem. (1979) 22 (1) pp. 63-69 and Chemical Abstract (1968) 70 (1) no.3722 T.

The same applies to a number of compounds having a benzo[b]thiophenenucleus: J. Med. Chem. (1970) 13 pp. 1205-1208, J. Heterocyclic Chem.(1978) 15 pp. 1351-1359, (1983) 20 pp. 1697-1703.

Benzo[b]furan analogues of melatonin have likewise been synthesised:Annalen (1963) 662 pp. 147-159 and patent FR 1343073, but nopharmacological activity of the melatoninomimetic type appears to havebeen found.

The same applies in the benzimidazole series, where demethoxylatedanalogues of melatonin have been prepared without such activityappearing to have been found: Khimiko Farmatsevticheskii Zhurnal (1968)9 pp. 21-23.

The Applicant has now found new compounds having an affinity for themelatonin receptors that is very considerably superior to that of theproducts described in the literature and to that of melatonin itself.

Those compounds possess numerous valuable pharmacological activities onaccount of their agonistic or antagonistic nature towards melatonin.

In addition to their beneficial action on disturbances in the circadianrhythm and sleep disorders and on seasonal disorders, they have valuablepharmacological properties on the central nervous system, especiallyanxiolytic, anti-psychotic and analgesic properties, and on ovulation,cerebral circulation and immunomodulation.

More specifically, the present invention relates to the compounds of thegeneral formula (I): ##STR2## in which: Ar' represents:

an indol-3-yl nucleus of formula (II): ##STR3## a benzo[b]thiophen-3-ylnucleus of formula (III): ##STR4## a benzimidazol-1-yl nucleus offormula (IV): ##STR5## a benzo[b]furan-3-yl nucleus of formula (V):##STR6## a 1,2-benzisoxazol-3-yl nucleus of formula (VI): ##STR7## a1,2-benzisothiazol-3-yl nucleus of formula (VII): ##STR8## anindazol-3-yl nucleus of formula (VIII): ##STR9## R₁ represents: a group##STR10## in which R₇ represents an optionally substituted cycloalkylradical, an optionally substituted cycloalkyl-(C₁ -C₄)alkyl radical, ora trifluoromethyl group,

and, when Ar' represents a group selected from those of formulae (IV),(VI), (VII) and (VIII), R₇ may also represents a linear or branchedalkyl radical having from 1 to 6 carbon atoms that is unsubstituted orsubstituted by 1 or 2 halogen radicals,

group ##STR11## in which R₈ represents a linear or branched lower alkylradical having from 1 to 6 carbon atoms, an optionally substitutedcycloalkyl radical, an optionally substituted cycloalkyl-(C₁ -C₄)-alkylradical, an optionally substituted aryl radical, or an optionallysubstituted arylalkyl radical the alkyl chain of which contains from 1to 3 carbon atoms, or

a group ##STR12## in which n represents an integer from 1 to 3 and E₁represents a radical selected from:

morpholino and

piperazine that is unsubstituted or substituted by a radical--(CH₂)_(n') --E₂ wherein n' represents an integer from 1 to 4 and E₂represents a phenyl or naphthyl radical each of which is unsubstitutedor substituted by from 1 to 3 radicals selected from: halogen, (C₁-C₄)alkyl and (C₁ -C₄)alkoxy;

R₂ represents a hydrogen atom or a linear or branched lower alkylradical having from 1 to 6 carbon atoms;

R₃ represents a hydrogen atom, a linear or branched lower alkyl radicalhaving from 1 to 6 carbon atoms, an optionally substituted aryl radical,an optionally substituted arylalkyl or diarylalkyl radical in which thealkyl chain contains from 1 to 3 carbon atoms, or a cycloalkyl orcycloalkylalkyl radical in which the alkyl chain contains from 1 to 3carbon atoms;

R₃ ' represents a hydrogen atom or a group --O--R₃ wherein R₃ is asdefined above;

R₄ represents a hydrogen atom, a halogen atom, a hydroxy radical, alinear or branched alkoxy radical having from 1 to 6 carbon atoms, or alinear or branched lower alkyl radical having from 1 to 6 carbon atoms;

R₅ represents a hydrogen atom, a halogen atom, a linear or branchedlower alkyl radical having from 1 to 6 carbon atoms, an optionallysubstituted phenyl radical, or an optionally substituted phenylalkylradical in which the alkyl chain contains from 1 to 3 carbon atoms; and

R₆ represents a hydrogen atom, or a linear or branched lower alkylradical having from 1 to 6 carbon atoms;

the isomers, epimers and diastereoisomers thereof,

and the addition salts thereof with a pharmaceutically acceptable acidor base,

with the provisos that:

Ar' may not represent a 7-methoxybenzo[b]furan-3-yl group when R₁represents a cyclopropylcarbonyl radical;

R₁ may not represent a trifluoroacetyl radical when Ar' represents anindole radical wherein R₂ =R₃ =R₄ =R₅ =R₆ =H;

and R₁ may not represent an anilinothiocarbonyl radical that isunsubstituted or substituted at the 4-position of the phenyl by analkoxy radical, when Ar represents an indol-3-yl nucleus and R₃represents a methyl or benzyl radical;

and wherein

the term "substituted" associated with the expressions "aryl","arylalkyl", "diarylalkyl", "phenyl" and "phenylalkyl" indicates thatthe aromatic nucleus or nuclei may be substituted by one or moreradicals selected from: linear or branched lower alkyl having from 1 to6 carbon atoms, linear or branched lower alkoxy having from 1 to 6carbon atoms, hydroxy, halogen, nitro, and trifluoromethyl;

the term "substituted" associated with the expressions "cycloalkyl" and"cycloalkyl-(C₁ -C₄)alkyl" indicates that the cyclic system may besubstituted by one or more radicals selected from: halogen, linear orbranched lower alkyl having from 1 to 6 carbon atoms, and linear orbranched lower alkoxy having from 1 to 6 carbon atoms;

the term "cycloalkyl" designates a saturated or unsaturated cyclicsystem having from 3 to 8 carbon atoms; and

the expression "aryl group" is understood as meaning a pyridyl, phenyl,naphthyl, thienyl, furyl or pyrimidyl group.

The present invention relates also to a process for the preparation ofthe compounds of formula (I), characterised in that there is used asstarting material an amine of the general formula (IX):

    Ar'--CH.sub.2 CH.sub.2 --NHR.sub.2                         (IX),

in which Ar' and R₂ have the same meaning as in formula (I), which istreated:

with an acid chloride of formula (X): ##STR13## or with thecorresponding acid anhydride of formula (XI): ##STR14## in whichformulae R₇ has the same meaning as in formula (I), to obtain thecompounds of formula (Iα): ##STR15## in which Ar', R₂ and R₇ have thesame meaning as in formula (I),

or with an isocyanate of formula (XII):

    R.sub.8 --N═C═O                                    (XII),

in which R₈ has the same meaning as in formula (I), to obtain thecompounds of formula (Iβ): ##STR16## in which Ar', R₂ and R₈ have thesame meaning as in formula (I),

or with an isothiocyanate of formula (XIII):

    R.sub.8 --N═C═S                                    (XIII),

in which R₈ has the same meaning as in formula (I), to obtain thecompounds of formula (Iγ): ##STR17## in which Ar', R₂ and R₈ have thesame meaning as in formula (I),

it being understood that the compounds of formulae (Iα), (Iβ), and (Iγ)form part of the invention and together constitute the compounds offormula (I),

it being possible for the compounds of formula (I) to be:

purified by one or more purification methods selected fromcrystallisation, chromatography over a silica column, extraction,filtration, and passage over carbon and/or resin,

separated, where applicable, in pure form or in the form of a mixture,into their possible optical isomers,

and/or converted into salts by means of a pharmaceutically acceptableacid or base.

The invention also includes a process for obtaining the compounds offormula (Iε): ##STR18## in which R₁ and R₂ are as defined in formula (I)and Ar" represents a group Ar' as defined in formula I) that issubstituted by a group --O--R₃ " wherein R₃ " represents a groupselected from optionally substituted aryl, optionally substitutedarylalkyl or diarylalkyl, and cycloalkyl or cycloalkylalkyl (the terms"aryl", "arylalkyl", "diarylalkyl", "cycloalkyl", "cycloalkylalkyl" and"substituted" being as defined in formula (I)), characterised in that acompound of formula (Iε'): ##STR19## in which R₁ and R₂ are as definedabove and Ar"' represents a group Ar' as defined in formula (I) that issubstituted by a group --O--R₃ '" wherein R₃ '" represents a hydrogenatom, is reacted with a compound of formula (XIV):

    R'--Hal                                                    (XIV),

in which Hal represents a halogen atom and R" represents a groupselected from optionally substituted aryl, optionally substitutedarylalkyl or diarylalkyl, and cycloalkyl or cycloalkylalkyl (the terms"aryl", "arylalkyl", "diarylalkyl", "cycloalkyl", "cycloalkylalkyl" and"substituted" being as defined in formula (I)),

it being possible for the compounds of formula (Iε) to be:

purified by one or more purification methods selected fromcrystallisation, chromatography over a silica column, extraction,filtration, and passage over carbon and/or resin,

separated, where applicable, in pure form or in the form of a mixture,into their possible optical isomers,

and/or converted into salts by means of a pharmaceutically acceptableacid or base.

The invention also includes a process for the preparation of thecompounds of formula (IΦ): ##STR20## in which Ar', R₂, E₁ and n are asdefined in formula (I), characterised in that a compound of formula(IΦ'): ##STR21## in which Ar', R₂ and n are as defined in formula (I)and Hal₁ represents a halogen atom, is reacted with a morpholine groupor with a piperazine group that is unsubstituted or substituted by aradical --(CH₂)_(n') --E₂ wherein n' and E₂ are as defined in formula(I),

it being possible for the compounds of formula (IΦ) to be:

purified by one or more purification methods selected fromcrystallisation, chromatography over a silica column, extraction,filtration, and passage over carbon and/or resin,

separated, where applicable, in pure form or in the form of a mixture,into their possible optical isomers,

and/or converted into salts by means of a pharmaceutically acceptableacid or base.

The amines of formula (IX) are either commercially available or readilyaccessible to the person skilled in the art.

The compounds of formula (I) have valuable pharmacological properties.

The pharmacological study of those compounds has in fact shown that theyhave low toxicity and a very high selective affinity for the melatoninreceptors (which is far superior to that of melatonin itself and to thatof its analogues described in the literature).

Among their important activities on the central nervous system, thecompounds of the invention have sedative, anxiolytic, anti-psychotic andanalgesic properties as well as properties affecting microcirculation,as a result of which they can be used in the treatment of stress, ofsleep disorders, of anxiety, of seasonal depression, of insomnia andfatigue due to jet lag, of schizophrenia, of panic attacks, ofmelancholia, of regulation of the appetite, of insomnia, of psychoticdisorders, of epilepsy, of Parkinson's disease, of senile dementia, ofdisorders associated with normal or pathological ageing, of migraine, ofmemory loss, of Alzheimer's disease and of disorders of cerebralcirculation.

The compounds of the invention also have ovulation-inhibiting andimmunomodulatory properties, which enable them to be used in thetreatment of certain cancers.

When administered externally, they may be used in the treatment ofpsoriasis, of acne and of seborrhoea, and they protect the skin.

They may also be used in veterinary medicine for their properties on thefur.

The present invention relates also to pharmaceutical compositionscontaining the products of formula (I) on their own or in combinationwith one or more inert, non-toxic, pharmaceutically acceptableexcipients or vehicles.

Of the pharmaceutical compositions according to the invention there maybe mentioned, by way of non-limiting examples, those which are suitablefor oral, parenteral, nasal, per- or trans-cutaneous, rectal,perlingual, ocular or respiratory administration, and especiallytablets, dragees, sublingual tablets, sachets, paquets, gelatincapsules, glossettes, lozenges, suppositories, creams, ointments, dermicgels, and injectable and drinkable ampoules.

The dosage varies according to the age and weight of the patient, themode of administration and the nature of the therapeutic indication orof any associated treatments, and ranges from 0.1 mg to 1 g per 24hours.

The following Examples illustrate the invention but do not limit it inany way.

EXAMPLE 1: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

3 g of 5-methoxytryptamine are added to a solution of 2.2 g of potassiumcarbonate in 40 cm³ of water. 80 cm³ of chloroform are added, and then1.7 g of cyclopropanecarboxylic acid chloride are added with veryvigorous stirring. After stirring at room temperature for 30 minutes,the organic phase is separated off, washed with water and then dried.

The resulting residue is crystallised in toluene, yielding 3.3 g (80.5%)of N-[2-(5-methoxyindol-3-yl)ethyl]-cyclopropylcarboxamide.

Melting point: 101°-102° C.

Infra-red (KBr disc): 3390 cm⁻¹ v NH indole;

3250-3300 cm⁻¹ v NH amide;

2900-3050 cm⁻¹ v CH alkyl;

1630 cm⁻¹ v CO amide

    ______________________________________                                        .sup.1 H-NMR 80 MHz (CDCl.sub.3)                                               ##STR22##                                                                    0.7-1     ppm    (5H)         cyclopropyl                                     2.8-3     ppm    (2H)         CH.sub.2 b                                      3.4-3.7   ppm    (2H)         CH.sub.2 a                                      3.8       ppm     (H)         OCH.sub.3                                       6.7-7.3   ppm    (4H)         indole                                          8.1       ppm    (1H)         NH (indole)                                     ______________________________________                                    

EXAMPLE 2:N-[2-(6-FLUORO-5-METHOXYINDOL-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 5-methoxy-6-fluorotryptamine (J. Heterocyclic Chem. (1976) 13 pp.1253-1256),N-[2-(5-methoxy-6-fluoroindol-3-yl)ethyl]-cyclopropylcarboxamide isobtained.

Melting point (dichloromethane-ether) : 125°-126° C.

EXAMPLE 3:N-[2-(6-CHLORO-5-METHOXYINDOL-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 5-methoxy-6-chlorotryptamine (Synthesis (1983) pp. 935-936),N-[2-(5-methoxy-6-chloroindol-3-yl)ethyl]-cyclopropylcarboxamide isobtained.

EXAMPLE 4:N-[2-(5-METHOXY-2,6-DIMETHYLINDOL-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 5-methoxy-2,6-dimethyltryptamine (Journal of Medicinal Chemistry(1973) 16 pp. 757-765),N-[2-(5-methoxy-2,6-dimethylindol-3-yl)ethyl]-cyclopropylcarboxamide isobtained.

EXAMPLE 5:N-[2-(5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxybenzo[b]thiophene (Journal of MedicinalChemistry (1970) 13 pp. 1205-1208),N-[2-(5-methoxybenzo[b]thiophen-3-yl)ethyl]-cyclopropylcarboxamide isobtained.

Melting point: 124°-126° C.

Infra-red (KBr disc): 3270 cm⁻¹ v NH amide;

1640 cm⁻¹ v CO amide

EXAMPLE 6:N-[2-(6-CHLORO-5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMID

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxy-6-chlorobenzo[b]thiophene (J. HeterocyclicChem. (1983) 20 pp. 1671-1703),N-[2-(5-methoxy-6-chlorobenzo[b]thiophen-3-yl)ethyl]-cyclopropylcarboxamide is obtained.

EXAMPLE 7:N-[2-(5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxybenzo[b]furan (Annalen (1963) 662 pp.147-159 or Aust. J. Chem. (1975) 28 pp. 1097-1111),N-[2-(5-methoxybenzo[b]furan-3-yl)ethyl]-cyclopropylcarboxamide isobtained.

Infra-red (KBr disc): 3290 cm⁻¹ v NH amide;

1680 cm⁻¹ v C═O amide

    ______________________________________                                        .sup.1 H-NMR 80 MHz (CDCl.sub.3)                                               ##STR23##                                                                    0.7-1     ppm    (5H)         cyclopropyl                                     2.9       ppm    (2H)         CH.sub.2 b                                      3.5-3.7   ppm    (2H)         CH.sub.2 a                                      3.9       ppm    (3H)         OCH.sub.3                                       6.8-7.3   ppm    (4H)         benzo[b]furan                                   ______________________________________                                    

EXAMPLE 8:N-[2-(2-METHYL-5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 2-methyl-3-β-aminoethyl-5-methoxybenzo[b]furan (Patent FR 1343073),N-[2-(2-methyl-5-methoxybenzo[b]furan-3-yl)ethyl]-cyclopropylcarboxamideis obtained.

Infra-red (KBr disc): 3320 cm⁻¹ v NH amide;

1650 cm⁻¹ v CO amide

EXAMPLE 9:N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 1-β-aminoethyl-6-methoxybenzimidazole (J. Chem. Soc. (1957) pp.1671-1674),N-[2-(6-methoxybenzimidazol-1-yl)ethyl]-cyclopropylcarboxamide isobtained.

Melting point (Ethyl acetate): 86°-88° C.

Infra-red (KBr disc): 3300 cm⁻¹ v NH amide;

1660 cm⁻¹ v CO amide

EXAMPLE 10:N-[2-(2-BENZYL-6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 1-β-aminoethyl-2-benzyl-6-methoxybenzimidazole (Patent FR 2182915),N-[2-(2-benzyl-6-methoxybenzimidazol-1-yl)ethyl]-cyclopropylcarboxamideis obtained.

EXAMPLE 11:N-[2-(5-METHOXY-1,2-BENZISOXAZOL-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxy-1,2-benzisoxazole (Chem. Pharm. Bull.(1976) 24 (4) pp. 632-643),N-[2-(5-methoxy-1,2-benzisoxazol-3-yl)ethyl]-cyclopropylcarboxamide isobtained.

EXAMPLE 12:N-[2-(5-METHOXY-1,2-INDAZOL-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxyindazole (J.A.C.S. (1957) 79 pp.5245-5247),N-[2-(5-methoxy-1,2-indazol-3-yl)ethyl]-cyclopropylcarboxamide isobtained.

EXAMPLE 13: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-TRIFLUOROACETAMIDE

1.14 g of trifluoroacetic acid are added dropwise to a suspension, at-5° C., of 1.90 g of 5-methoxytryptamine in 6 cm³ of pyridine. Themixture is stirred at room temperature for 30 minutes and then thereaction medium is poured onto ice-water. The resulting precipitate isisolated by filtration, washed with water, dried and then recrystallisedin toluene.

1.14 g (40%) of N-[2-(5-methoxyindol-3-yl)ethyl]-trifluoroacetamide areobtained.

Melting point: 135°-136° C.

Infra-red (KBr disc): 3400 cm⁻¹ v NH indole;

3300 cm⁻¹ v NH amide;

1700 cm⁻¹ v C═O

    ______________________________________                                        .sup.1 H-NMR 80 MHz (CDCl.sub.3)                                               ##STR24##                                                                    3        ppm    (2H)         CH.sub.2 b                                       3.6      ppm    (2H)         CH.sub.2 a                                       3.8      ppm    (3H)         OCH.sub.3                                        6.8-7.3  ppm                 aromatic protons                                 ______________________________________                                    

EXAMPLE 14:N-[2-(5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-TRIFLUOROACETAMIDE

Following the procedure of Example 13 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxybenzo[b]thiophene,N-[2-(5-methoxybenzo[b]thiophen-3-yl)ethyl]-trifluoroacetamide isobtained.

Infra-red (KBr disc): 3280 cm⁻¹ v NH amide;

1690 cm⁻¹ v C═O

EXAMPLE 15: N-[2-(5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-TRIFLUOROACETAMIDE

Following the procedure of Example 13 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxybenzo[b]furan,N-[2-(5-methoxybenzo[b]furan-3-yl)ethyl]-trifluoroacetamide is obtained.

Infra-red (KBr disc): 3290 cm⁻¹ v NH amide;

1700 cm⁻¹ v C═O amide

EXAMPLE 16: N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-TRIFLUOROACETAMIDE

Following the procedure of Example 13 but replacing with5-methoxytryptamine with 1-β-aminoethyl-6-methoxybenzimidazole,N-[2-(6-methoxybenzimidazol-1-yl)ethyl]-trifluoroacetamide is obtained.

Infra-red (KBr disc): 3300 cm⁻¹ v NH amide;

1690 cm⁻¹ v C═O amide

EXAMPLE 17:N-[2-(5-METHOXY-1,2-BENZISOXAZOL-3-YL)ETHYL]-TRIFLUOROACETAMIDE

Following the procedure of Example 13 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxy-1,2-benzisoxazole,N-[2-(5-methoxy-1,2-benzisoxazol-3-yl)ethyl]-trifluoroacetamide isobtained.

EXAMPLE 18: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-PROPYLUREA

0.851 g of propyl isocyanate is added to a suspension of 1.902 g of5-methoxytryptamine in 4 cm³ of pyridine at +5° C. The mixture isstirred at room temperature for 2 hours and then the reaction medium ispoured onto ice-water. The mixture is acidified slightly with a 1Nhydrochloric acid solution. The resulting precipitate is isolated byfiltration, washed with water, dried and then recrystallised in toluene,yielding 2.34 g (85%) of N-[2-(5-methoxyindol-3-yl)ethyl]-N'-propylurea.

Melting point: 79°-80° C.

    ______________________________________                                        .sup.1 H-NMR 80 MHz (CDCl.sub.3)                                               ##STR25##                                                                    0.9      ppm    (3H)         CH.sub.3 e                                       1.4      ppm    (2H)         CH.sub.2 d                                       2.9      ppm    (4H)         CH.sub.2 a CH.sub.2 c                            3.4      ppm    (2H)         CH.sub.2 b                                       3.9      ppm    (3H)         OCH.sub.3                                        6.6-7.3  ppm                 aromatic protons                                 ______________________________________                                    

EXAMPLE 19: N-[2-(5-METHOXYBENZO[b]THIOPHEN 3-YL)ETHYL]-N'-PROPYLUREA

Following the procedure of Example 18 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxybenzo [b]thiophene,N-[2-(5-methoxybenzo[b]thiophen-3-yl)ethyl]-N'-propylurea is obtained.

Infra-red (KBr disc): 3300 cm⁻¹ v NH;

1620 cm⁻¹ v C═O

EXAMPLE 20: N-[2-(6-CHLORO-5-METHOXYINDOL-3-YL)ETHYL]-N'-PROPYLUREA

Following the procedure of Example 18 but replacing 5-methoxytryptaminewith 5-methoxy-6-chlorotryptamine, N-[2-(5-methoxy-6-chloroindol-3-yl)ethyl]-N'-propylurea is obtained.

Infra-red (KBr disc): 3250 cm⁻¹ v NH;

1620 cm⁻ 1 v C═O

    ______________________________________                                        .sup.1 H-NMR 80 MHz (CDCl.sub.3)                                               ##STR26##                                                                    0.9-1    ppm    (3H)           CH.sub.3 e                                     1.5      ppm    (2H)           CH.sub.2 d                                     2.8-3    ppm    (4H)           CH.sub.2 b CH.sub.2 c                          3.4      ppm    (2H)           CH.sub.2 a                                     3.90     ppm    (3H)           OCH.sub.3                                      ______________________________________                                    

EXAMPLE 21: N-[2-(5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-N'-PROPYLUREA

Following the procedure of Example 18 but replacing 5-methoxytryptaminewith 3-β-aminoethyl-5-methoxybenzo[b]furan,N-[2-(5-methoxybenzo[b]furan-3-yl)ethyl]-N'-propylurea is obtained.

Infra-red (KBr disc): 3290 cm⁻¹ v NH;

1620 cm⁻¹ v C═O

EXAMPLE 22: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-PROPYLTHIOUREA

1.11 g of propyl isothiocyanate are added to a suspension of 2.27 g of5-methoxytryptamine in 5 cm³ of pyridine.

The reaction medium is stirred at 80° for one hour and then, aftercooling, is poured onto a mixture of water and ice and acidifiedslightly with a 1N hydrochloric acid solution.

The resulting precipitate is isolated by filtration, washed with water,dried and then recrystallised in toluene.

In this manner, 2.18 g (75%) ofN-[2-(5-methoxyindol-3-yl)ethyl]-N'-propylthiourea are obtained.

    ______________________________________                                        .sup.1 H-NMR 80 MHz (CDCl.sub.3)                                               ##STR27##                                                                    0.85    ppm    (3H)     CH.sub.3 e                                            1.45    ppm    (2H)     CH.sub.2 d                                            2.95    ppm    (4H)     CH.sub.2 c CH.sub.2 a                                 3.4     ppm    (2H)     CH.sub.2 b                                            3.85    ppm    (3H)     OCH.sub.3                                             5,50    ppm    (2H)                                                                                    ##STR28##                                                                              disappears in D.sub.2 O                     6.7-7.3 ppm     aromatic protons                                              ______________________________________                                    

EXAMPLE 23: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-CYCLOBUTYLCARBOXAMIDE

Following the procedure of Example 1 but replacingcyclopropanecarboxylic acid chloride with cyclobutanecarboxylic acidchloride, the title compound is obtained.

Melting point: 111°-112° C.

Crystallisation solvent: chloroform-acetone

EXAMPLES 24 TO 25

Following the procedure of Example 1 but replacingcyclopropanecarboxylic acid chloride with the appropriate acid chlorideor, where applicable, its corresponding acid anhydride, the compounds ofthe following Examples are obtained:

EXAMPLE 24: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-CYCLOHEXYLCARBOXAMIDE

EXAMPLE 25: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-3-CYCLOPENTYLPROPIONAMIDE

EXAMPLE 26: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-MORPHOLINOACETAMIDE

Step I: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-BROMOACETAMIDE

Following the procedure of Example 1 but replacingcyclopropanecarboxylic acid chloride with bromoacetic acid chloride,N-[2-(5-methoxyindol-3-yl)ethyl]-bromoacetamide is obtained.

Step II: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-MORPHOLINOACETAMIDE

0.01 mol of morpholine is dissolved in 50 cm³ of acetone, with magneticstirring. 0.012 mol of triethylamine and 0.01 mol ofN-[2-(5-methoxyindol-3-yl)ethyl]-2-bromoacetamide are added. The mixtureis refluxed for one hour with magnetic stirring. The resultingprecipitate is suction filtered and the filtrate is evaporated.

The residue is taken up in alkaline water, and the precipitate issuction filtered, washed, dried and recrystallised in atoluene-cyclohexane mixture, yielding the title compound.

EXAMPLES 27 AND 28

Following the procedure of Example 26 but replacing morpholine in stepII with 1-benzylpiperazine and then with1-(2,3,4-trimethoxybenzyl)piperazine, the compounds of the followingExamples are obtained in succession:

EXAMPLE 27:N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-2-(4-BENZYLPIPERAZIN-1-YL)ACETAMIDE

EXAMPLE 28:N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-2-(4-(2,3,4-TRIMETHOXYBENZYL)PIPERAZIN-1-YL)ACETAMIDE

EXAMPLE 29: N-[2-(5-HYDROXYINDOL-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

Following the procedure of Example 1 but replacing 5-methoxytryptaminewith 5-hydroxytryptamine, the title compound is obtained.

EXAMPLE 30:N-{2-[5-(CYCLOHEXEN-3-YLOXY)INDOL-3-YL]ETHYL}-CYCLOPROPYLCARBOXAMIDE

1.98×10⁻² mol of potassium carbonate, 1.33×10⁻² mol ofN-[2-(5-hydroxyindol-3-yl)ethyl]cyclopropylcarboxamide dissolved in 20cm³ of anhydrous acetone, and 2.1×10⁻² mol of 3-bromocyclohexene areintroduced into a 50 cm³ flask with a ground neck. The mixture is heatedunder reflux for 22 hours. The reaction medium is filtered and thefiltrate is evaporated under reduced pressure. Recrystallisation of theevaporation residue in ethyl acetate yields purifiedN-{2-[5-(cyclohexen-3-yloxy)indol-3-yl]ethyl}-cyclopropylcarboxamide.

EXAMPLE 31: N-[2-(5-BENZYLOXYINDOL-3-YL)ETHYL]-CYCLOPROPYLCARBOXAMIDE

0.23 g of sodium is introduced in small portions, with magneticstirring, into a 150 cm³ flask containing 50 cm³ of absolute ethanol.

0.01 mol of N-[2-(5-hydroxyindol-3-yl)ethyl]-cyclopropylcarboxamide isthen added, stirring is continued for 30 minutes, and then the mixtureis evaporated to dryness.

The resulting sodium compound is dissolved in 30 cm³ of anhydrousdimethylformamide. 0.011 mol of benzyl bromide is added, with magneticstirring, by means of a dropping funnel.

The mixture is heated at 90° C. for 4 hours. The reaction medium isallowed to cool and is then poured onto ice. The resulting precipitateis suction filtered and washed with a 1N sodium hydroxide solution andthen with water. The mixture is dried and recrystallised, yieldingpurified N-[2-(5-benzyloxyindol-3-yl)ethyl]-cyclopropylcarboxamide.

EXAMPLES 32 TO 37

Following the procedure of Example 18 but replacing propyl isocyanatewith the appropriate isocyanates or isothiocyanate, the compounds of thefollowing Examples are obtained:

EXAMPLE 32: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-BENZYLUREA

EXAMPLE 33: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-CYCLOPROPYLUREA

EXAMPLE 34: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-CYCLOBUTYLUREA

EXAMPLE 35: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-BUTYLUREA

EXAMPLE 36: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-PROPYLTHIOUREA

EXAMPLE 37: N-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-CYCLOHEXYLTHIOUREA

EXAMPLES 38 AND 39

Following the procedure of Example 5 but replacingcyclopropanecarboxylic acid chloride with the appropriate acid chlorideor acid anhydride, the compounds of the following Examples are obtained:

EXAMPLE 38:N-[2-(5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-CYCLOBUTYLCARBOXAMIDE

EXAMPLE 39:N-[2-(5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-CYCLOOCTYLCARBOXAMIDE

EXAMPLES 40 AND 41

Following the procedure of Example 19 but replacing propyl isocyanatewith the appropriate isocyanate or isothiocyanate, the compounds of thefollowing Examples are obtained:

EXAMPLE 40:N-[2-(5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-N'-CYCLOPROPYLUREA

EXAMPLE 41:N-[2-(5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-N'-CYCLOHEXYLTHIOUREA

EXAMPLES 42 AND 43

Following the procedure of Example 6 but replacingcyclopropanecarboxylic acid chloride with the appropriate acid chloride,the compounds of the following Examples are obtained:

EXAMPLE 42:N-[2-(6-CHLORO-5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-CYCLOBUTYLCARBOXAMIDE

EXAMPLE 43:N-[2-(6-CHLORO-5-METHOXYBENZO[b]THIOPHEN-3-YL)ETHYL]-3-CYCLOPENTYLPROPIONAMIDE

EXAMPLES 44 TO 46

Following the procedure of Example 7 but replacingcyclopropanecarboxylic acid chloride with the appropriate acidchlorides, the compounds of the following examples are obtained:

EXAMPLE 44: N-[2-(BENZO[b]FURAN-3-YL)ETHYL]-CYCLOBUTYLCARBOXAMIDE

EXAMPLE 45: N-[2-(BENZO[b]FURAN-3-YL)ETHYL]-CYCLOHEXYLCARBOXAMIDE

EXAMPLE 46: N-[2-(BENZO[b]FURAN-3-YL)ETHYL]-TRIFLUOROACETAMIDE

EXAMPLES 47 TO 51

Following the procedure of Example 21 but replacing propyl isocyanatewith the appropriate isocyanate or isothiocyanate, the compounds of thefollowing Examples are obtained:

EXAMPLE 47: N-[2-(5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-N'-METHYLUREA

EXAMPLE 48: N-[2-(5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-N'-ETHYLUREA

EXAMPLE 49: N-[2-(5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-N'-HEXYLUREA

EXAMPLE 50: N-[2-(5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-N'-BENZYLUREA

EXAMPLE 51: N-[2-(5-METHOXYBENZO[b]FURAN-3-YL)ETHYL]-N'-PROPYLTHIOUREA

EXAMPLES 52 TO 54

Following the procedure of Example 11 but replacingcyclopropanecarboxylic acid chloride with the appropriate acid chloride,the compounds of the following Examples are obtained:

EXAMPLE 52: N-[2-(5-METHOXY-1,2-BENZISOXAZOL-3-YL)ETHYL]-ACETAMIDE

EXAMPLE 53: N-[2-(5-METHOXY-1,2-BENZISOXAZOL-3-YL)ETHYL]-BUTYRAMIDE

EXAMPLE 54:N-[2-(5-METHOXY-1,2-BENZISOXAZOL-3-YL)ETHYL]-3-CHLOROPROPIONAMIDE

EXAMPLES 55 AND 56

Following the procedure of Example 12 but replacingcyclopropanecarboxylic acid chloride with the appropriate acid chloride,the compounds of the following Examples are obtained:

EXAMPLE 55: N-[2-(5-METHOXY-1,2-INDAZOL-3-YL)ETHYL]-ACETAMIDE

EXAMPLE 56: N-[2-(5-METHOXY-1,2-INDAZOL-3-YL)ETHYL]-PROPIONAMIDE

EXAMPLES 57 TO 60

Following the procedure of Example 9 but replacingcyclopropanecarboxylic acid chloride with the corresponding acidchloride, the compounds of the following Examples are obtained:

EXAMPLE 57: N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-ACETAMIDE

Melting point: 173°-175° C.

EXAMPLE 58: N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-BUTYRAMIDE

EXAMPLE 59: N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-PENTANAMIDE

EXAMPLE 60: N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-2-BROMOACETAMIDE

EXAMPLES 61 TO 65

Following the procedure of Example 16 but replacing propyl isocyanatewith the appropriate isocyanates or isothiocyanates, the compounds ofthe following Examples are obtained:

EXAMPLE 61: N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-N'-PROPYLUREA

EXAMPLE 62: N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-N'-BENZYLUREA

EXAMPLE 63: N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-N'-PROPYLTHIOUREA

EXAMPLE 64:N-[2-(6-METHOXYBENZIMIDAZOL-1-YL)ETHYL]-N'-CYCLOHEXYLTHIOUREA

EXAMPLE 65: N-[2-(6-METHOXYBENZIMIDAZOL-3-YL)ETHYL]-N'-PROPYLUREA

Melting point (dichloromethane-ether): 109°-110° C.

EXAMPLE A: DETERMINATION OF BINDING TO MELATONIN RECEPTORS

The binding of the compounds of the invention to melatonin receptors wascarried out according to conventional methods on receptors of the parstuberalis of sheep (Journal of Neuroendocrinology, Vol. 1, No. 1, pp.1-4 (1989)).

The compounds of the invention bind in an extremely specific manner tothe melatonin receptors with an affinity, for those exhibiting the mostaffinity, that is more than 100 times greater than that of melatoninitself. The compounds of the invention which were tested have adissociation constant (Kd) of the order of 10⁻¹³ mol.1⁻¹, as comparedwith 6.3×10⁻¹¹ mol.1⁻¹ for melatonin itself.

EXAMPLE B: FOUR-PLATE TEST

The products of the invention are administered by the oesophageal routeto groups of ten mice. One group receives gum syrup.

30 minutes after the administration of the products to be studied, theanimals are placed in containers the floors of which comprise four metalplates. Each time the animal passes from one plate to another, itreceives a slight electric shock (0.35 mA). The number of passages isrecorded for a period of one minute. After administration, the compoundsof the invention increase significantly the number of passages, whichindicates the anxiolytic activity of the compounds of the invention.

EXAMPLE C: ACTIVITY OF THE PRODUCTS OF THE INVENTION ON ISCHAEMICMICROCIRCULATION

The experimental study was carried out on the cremaster muscles of malerats (Sprague-Dawley) following ligature of the common iliac artery.

The muscles were placed in a transparent chamber and perfused with asolution of bicarbonate buffer equilibrated with a gaseous CO₂ /N₂mixture 5/95%. The velocity of the red corpuscles and the diameter ofthe first- or second-order arterioles irrigating the cremaster weremeasured, and the arterial blood flow was calculated. Identicalinformation was obtained for four types of vessels.

The same type of measurement was carried out simultaneously:

on the cremaster perfused normally,

on the cremaster after ligature, that is to say the ischaematisedcremaster, 2, 7, 14 and 21 days following ligature.

Two groups of animals were studied:

a control group without treatment,

a group treated p.o. with a product of the invention, at a dose of 0.1mg.kg⁻¹ per day.

No difference was noted in either the velocity of the corpuscles or thediameter of the vessels in the normally irrigated cremaster muscles inthe treated animals as compared with the controls.

On the other hand, at the level of the ischaematised cremaster muscle,the mean diameter of the arterioles was improved in the treated animalsas compared with the controls. The velocity of the red corpuscles wasnormalised by treatment for 21 days.

In fact, in the treated animals, the velocity of the red corpuscles andthe blood flow measured 7 days after ligature show no significantdifference as compared with the values obtained in the non-ischaematisedcremaster. These results are obtained without modification of thearterial pressure.

These results indicate that chronic treatment with one of the compoundsof the invention improves microcirculation and blood irrigation of theischaemic regions.

EXAMPLE D: STIMULATION OF IMMUNE RESPONSES

Red corpuscles of sheep were administered to groups of six mice. Thosegroups of mice were then treated subcutaneously with the compounds ofthe invention for a period of six days, and a control group was treatedwith a placebo. The mice are then left for four weeks and then receiveda repeat injection of red corpuscles of sheep without receiving furtheradministrations of the product of the invention. The immune response wasevaluated 3 days after the repeat injection. It is statisticallyincreased in the group treated with the compounds of the invention.

EXAMPLE E: INHIBITION OF OVULATION

Adult female rats with regular four-day cycles are used. Vaginal smearswere taken daily, and rats were selected after they had exhibited atleast two consecutive four-day cycles.

Each cycle is composed of two days of dioestrus, one day of pro-oestrusand one day of oestrus.

On the afternoon of the day of pro-oestrus, luteinizing hormone isreleased into the blood by the hypophysis.

This hormone induces ovulation, which is indicated by the presence ofeggs at the oviduct on the day of oestrus.

The compounds of the invention are administered orally at mid-day on theday of oestrus. The treated rats and the controls are sacrificed on theday of oestrus. The oviducts are examined. A significant percentagereduction in the number of eggs in the oviducts of rats treated with thecompounds of the invention is noted.

EXAMPLE F: PHARMACEUTICAL COMPOSITION Tablets containing 5 mg ofN-[2-(5-METHOXYINDOL-3-YL)ETHYL]-N'-PROPYLUREA

Preparation formulation for 1000 tablets:

    ______________________________________                                        N-[2-(5-methoxyindol-3-yl)ethyl]-N'-propylurea                                                            5 g                                               wheat starch                20 g                                              corn starch                 20 g                                              lactose                     30 g                                              magnesium stearate          2 g                                               silica                      1 g                                               hydroxypropylcellulose      2 g                                               ______________________________________                                    

We claim:
 1. A compound selected from those of the formula (I):##STR29## in which: Ar' represents:indol-3-yl of formula (II): ##STR30##R₁ represents: a group ##STR31## in which R₇ represents unsubstituted oroptionally substituted cycloalkyl, unsubstituted or optionallysubstituted cycloalkyl-(C₁ -C₄)alkyl, or trifluoromethyl, a group##STR32## in which R₈ represents linear or branched lower alkyl having 1to 6 carbon atoms, inclusive, unsubstituted or optionally substitutedcycloalkyl, unsubstituted or optionally substituted cycloalkyl-(C₁-C₄)alkyl, or unsubstituted or optionally substituted arylalkyl in whichthe alkyl chain contains 1 to 3 carbon atoms, inclusive, or a group##STR33## in which n represents 1 to 3 inclusive and E₁ represents aradical selected from: morpholino and piperazine, which radical isunsubstituted or substituted by a radical --(CH₂)_(n') --E₂ wherein n'represents 1 to 4 inclusive and E₂ represents phenyl or naphthyl, eachof which is unsubstituted or substituted by 1 to 3 radicals inclusiveselected from: halogen, (C₁ -C₄)alkyl, and (C₁ -C₄)alkoxy; R₂ representshydrogen or linear or branched lower alkyl having 1 to 6 carbon atomsinclusive; R₃ represents hydrogen, linear or branched lower alkyl having1 to 6 carbon atoms inclusive, unsubstituted or optionally substitutedaryl, unsubstituted optionally substituted arylalkyl or diarylalkyl inwhich the alkyl chain contains 1 to 3 carbon atoms, inclusive, orcycloalkyl or cycloalkylalkyl in which the alkyl chain contains 1 to 3carbon atoms, inclusive, R₄ represents hydrogen, halogen, hydroxy,linear or branched alkoxy having 1 to 6 carbon atoms, inclusive, orlinear or branched lower alkyl having 1 to 6 carbon atoms, inclusive, R₅represents hydrogen, halogen, linear or branched lower alkyl having 1 to6 carbon atoms, inclusive, unsubstituted or optionally substitutedphenyl, or unsubstituted optionally substituted phenylalkyl in which thealkyl chain contains 1 to 3 carbon atoms, inclusive, and R₆ representshydrogen, or linear or branched lower alkyl having 1 to 6 carbon atoms,inclusive; an optical isomer, and an addition salt thereof with apharmaceutically-acceptable acid or base, with the provisos that:R₁ maynot represent trifluoroacetyl when Ar' represents indole wherein R₂ =R₃=R₄ =R₅ =R₆ =H; and R₁ may not represent an anilinothiocarbonyl that isunsubstituted or substituted at the 4-position of the phenyl radical byalkoxy, when Ar' represents indol-3-yl and R₃ represents methyl orbenzyl;and wherein the term "substituted" associated with theexpressions "aryl", "arylalkyl", "diarylalkyl", "phenyl" and"phenylalkyl" means that the aromatic nucleus or nuclei may besubstituted by one or more radicals selected from: linear or branchedlower alkyl having 1 to 6 carbon atoms, inclusive, linear or branchedlower alkoxy having 1 to 6 carbon atoms, inclusive, hydroxy, halogen,nitro, and trifluoromethyl; the term "substituted" associated with theexpressions "cycloalkyl" and "cycloalkyl-(C₁ -C₄)alkyl" means that thecyclic system may be substituted by one or more radicals selected from:halogen, linear or branched lower alkyl having 1 to 6 carbon atoms,inclusive, and linear or branched lower alkoxy having 1 to 6 carbonatoms, inclusive; the term "cycloalkyl" designates a saturated orunsaturated cyclic system having 3 to 8 carbon atoms, inclusive, and theexpression "aryl group" means pyridyl, phenyl, naphthyl, thienyl, furyl,or pyrimidyl.
 2. A compound according to claim 1 selected from those inwhich Ar' represents an indol-3-yl radical, which corresponds to one ofthe indoles of the formula: ##STR34## in which R₂, R₅ and R₆ have thesame meanings as in claim 1, andR₁ represents:--CO--NH lower-alkyl,--CS--NH lower-alkyl, --CO--CF₃, or --CO-- cyclo-alkyl, R₃ islower-alkyl, and R₄ is hydrogen or fluoro,an optical isomer, and anaddition salt thereof with a pharmaceutically-acceptable acid or base.3. A compound according to claim 1 which isN-[2-(5-methoxyindol-3-yl)ethyl]-trifluoroacetamide.
 4. A compoundaccording to claim 1 which isN-[2-(5-methoxyindol-3-yl)ethyl]-N'-propylurea.
 5. A compound accordingto claim 1 which is N-[2-(5-methoxyindol-3-yl)ethyl]-N'-propylthiourea.6. A compound according to claim 1 which isN-[2-(5-methoxyindol-3-yl)ethyl]-cyclopropylcarboxamide.
 7. A compoundaccording to claim 1 which isN-[2-(5-methoxyindol-3-yl)ethyl]-cyclobutylcarboxamide.
 8. A compoundaccording to claim 1 which isN-[2-(6-fluoro-5-methoxyindol-3-yl)ethyl]-cyclopropylcarboxamide.
 9. Acompound according to claim 1 which isN-[2-(6-fluoro-5-methoxyindol-3-yl)ethyl]-N'-propylurea.
 10. Apharmaceutical composition useful in treating or in preventing adisorder of the melatoninergic system containing as active principle aneffective amount of a compound as claimed in claim 1, in combinationwith one or more pharmaceutically-acceptable excipients or vehicles. 11.A method of treating a mammal afflicted with a disorder of themelatoninergic system comprising the step of administering to the saidmammal an amount of a compound as claimed in claim 1 which is effectivefor alleviation of said disorder.